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Liver Disease Affects Metformin Metabolism

Increased diabetes drug exposure may increase risk of adverse reactions in type 2 patients with NASH…

Obesity increases the risk of nonalcoholic steatohepatitis (NASH), which occurs when there is too much fat in the liver. NASH is often asymptomatic and because testing for it requires a liver biopsy, many cases go undiagnosed. It is estimated that between 6 and 17 percent of Americans currently have NASH. With obesity on the rise, that number will continue to grow.

While it is known that NASH can affect hepatic clearance of drugs, researchers at the University of Arizona College of Pharmacy decided to study how NASH affects kidney transporters such as Oct1, Oct2, and Mate1, which are primarily responsible for the elimination of metformin.

Using mouse models of obesity, diabetes, NASH, and a choline and methionine deficient diet, the researchers found that this caused decreases in Oct2 and Mate1 expression in the kidneys, leading to a 4.8-fold increase in serum metformin levels.

“This study, in addition to several of our other recent studies shows that NASH, either alone or in combination with genetic differences in drug transporters, can have a profound effect on drug exposure,” said research associate John Clarke. Nathan Cherrington, professor at the university’s Department of Pharmacology and Toxicology, adds that the next step is to continue the research to demonstrate that NASH can lead to metformin retention in humans.

While metformin is considered a relatively safe and effective drug, increased exposure may increase the risk of adverse reactions. “If any clinician is going to provide precision medicine, they’ll need to know the ability of the liver and kidneys to metabolize and eliminate drugs,” says Cherrington. He believes this study will lead to better individualized medicine, where a patient receives the exactly appropriate dose of metformin based on their specific ability to metabolize and clear the drug.

Practice Pearls:

  • Obesity is a risk factor for NASH, which is caused by too much fat in the liver.
  • NASH is often undiagnosed.
  • NASH can cause retention of metformin for a longer period of time for some and at increased serum concentrations. Treatment should be individualized.

Clarke JD, Dzierlenga AL, Nelson NR, Li H, Werts S, Goedken MJ, Cherrington NJ. “Mechanism of altered metformin distribution in nonalcoholic steatohepatitis.” Abstract. ADA Diabetes. Published online 27 May 2015.